The peripheral nervous system (PNS) is a key affecter of proliferative and inflammatory processes after injury. Neuropeptides (NPs) from the PNS modulate cytokine responses and control local blood flow. Our preliminary studies show NPs has a prominent role in ligament healing. We show peripheral neuropathies significantly degrade mechanical strength of healing tissues. We also show local delivery of NPs to a transected ligament dramatically improves functional recovery (i.e. strength and stiffness). After only two weeks of healing with adjuvant NPs, healing ligaments exceed the strength of even their sham-operated (but not transected) controls. This level of healing dramatically exceeds any published study of normal healing or augmented healing in ligaments or tendons (better than stem cell augmentation, better than growth factors, and better than increased hemorrhage). Because NPs profoundly influence cellular repopulation during healing, they may establish an entirely new paradigm for tissue engineering. However, before NPs can be effectively used, we must elucidate their specific and combinatorial roles on healing tissues and grafts. Therefore, our objectives are: 1) In a healing ligament model, define the influence of sympathetic and sensory NPs on functional recovery (i.e. ligament strength, stiffness, and laxity). 2) Study the biological mechanisms by which NPs have this remarkable effect on ligament healing (i.e. collagen microstructure, cell proliferation, blood flow, as well as anabolic and catabolic agents in the extra-cellular matrix). 3) Demonstrate the role of NPs to augment healing in a ligament graft model (quantified as above). 4) Study the biological mechanisms by which NPs affect ligament graft healing (quantified as above). Ligaments are chosen as our experimental model due to their simplicity and well-defined healing behavior. Rat medial collateral ligament (MCL), anterior cruciate ligament (ACL), and ACL graft tissue (hamstring tendon) will be used. No PNS neuropathies will be created other than those induced by MCL transection and ACL graft harvest and reconstruction. This study will be the first to optimize NP concentrations relative to ECM healing and the first to define the combinatorial effect of NPs on tissue and tissue graft healing. We expect this study to significantly impact the scientific basis and the treatment of: ligament and tendon healing, ligament and tendon grafting, as well as many, associated tissue engineering applications. [unreadable] [unreadable]